The present invention relates to an improved process for the preparation of cefixime of formula (I), with an improved quality having better color and solubility. Cefixime (I) is an orally active third-generation cephalosporin antibiotic and is more potent against gram-negative bacteria.
The process for the preparation of the cefixime of formula (I), is disclosed in U.S. Pat. No. 6,825,345 B2 (WO 99/51607) and U.S. Pat. No. 4,409,214 which involves condensation of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (II) with the benzothiazolyl ester of (Z)-2-(2-amino-4-thiazolyl)-(Z)-2-(aryl/alkoxycarbonylmethoxyimino)acetic acid (III, R1 represents (C1-C4) alkyl group or aryl group) to produce ester compound of formula (IV) wherein R1 represents (C1-C4) alkyl group or aryl group and R2 represents hydrogen; followed by hydrolysis to produce cefixime of the formula (I).

GB 2 330 140 discloses a process for the preparation of cefixime of formula (I) which comprises treating cefixime methyl ester of formula (IV) wherein R1 represents methyl and R2 represents hydrogen with an inorganic base such as K2CO3 or Na2CO3 in mixture of dimethylformamide (DMF) and water, which has the following problems: (i) color and quality are poor, (ii) fails in residual solvent (i.e. DMF).
GB 2 330 141 discloses a process for the preparation of the compound of formula (I) which comprises treating cefixime methyl ester of formula (IV) wherein R1 represents methyl and R2 represents hydrogen in an organic solvent such as dichloromethane with aqueous solution of inorganic base such as K2CO3 or Na2CO3 and phase transfer catalyst such as quaternary ammonium salts of general formula R4N+X− wherein R is n-butyl, n-pentyl, n-hexyl and X is Cl−, Br−I− or OH−. We found that the color, quality and yield of the product obtained from bi-phasic reaction are poor.
The U.S. Pat. No. 4,409,214 and EP 0,763,043 (derived from WO 95/33753) discloses the process for the preparation of cefixime of formula I by hydrolysis of cefixime diester of formula (IV) wherein R1 and R2 both represent tert.butyl, by using hazardous trifluoroacetic acid and anisole.
The PCT application WO 99/052 913 discloses the hydrolysis of cefixime diester of formula (IV) wherein R1 represents tert.butyl and R2 represents naphthylmethyl, by using phenol and protonic acid.
The U.S. Pat. No. 6,800,755 B2 particularly discloses the process of preparation of cefixime of formula I from cefixime ester (IV) wherein R1=C1-C4 alkyl group and R2 represents hydrogen, by hydrolysis with sodium hydroxide in water-water immiscible solvent such as ethyl acetate.
The publication J. Antibiotics (1985), 38, 1738 discloses various processes for the preparation of cefixime of formula (I) and the processes for purification that involve use of column chromatography. The purification by column chromatography cannot be used in large-scale operations, there by making the process commercially not viable.
The steps described in the above publications are more complicated and also suffer from low yield and poor quality.
The inventors have directed their research efforts towards developing a process for the preparation of cefixime which overcome not only the drawbacks of the prior art but which is operationally simple and reproducible on an industrial scale, moreover it gives cefixime trihydrate possessing good quality, colour and solubility profile.
Further the process of present invention avoids use large amounts of solvents for the coupling process as mentioned in the prior-art methods, and thus makes it commercially viable.